PROJECT SUMMARY This K23 application is submitted by Andrea A. Berry, M.D., an Assistant Professor of Pediatrics at the University of Maryland School of Medicine. Dr. Berry's long term goal is to become an independent investigator in the field of malaria translational research. Towards this goal, she proposes a mentored career development plan that provides training in microarray analysis, biostatistics, and epidemiology. An effective Plasmodium falciparum malaria vaccine will boost prospects for the control and eventual eradication of malaria. However, the field is only beginning to understand the requirements and characteristics of malaria protective immunity, which is key to vaccine development. A promising approach is serological profiling on high-throughput protein microarrays, which can elucidate antibody responses to hundreds of P. falciparum antigen variants simultaneously. The investigator's group uses protein microarrays containing diverse variants of key P. falciparum antigens so that they can study antigen variants associated with cross- reactive and cross-protective immune responses. However, a gap in knowledge is the ability to differentiate between antibody binding due to cross-reactivity and antibody binding due to accumulated exposure to malaria ? on protein microarrays, both responses manifest as reactivity to multiple antigen variants. Differentiating these two patterns of antibody binding is difficult in field studies because only limited data is available on participants' previous exposure, and even for ongoing infections one cannot always know the exact genetic makeup of the parasite or the exact timing of exposure. Elucidating the characteristics of cross-reactivity and accumulated exposure is nonetheless critical to gaining a better understanding of the development of protective immunity from malaria. Controlled Human Malaria Infections, in which volunteers are exposed to malaria through the bites of infectious mosquitoes, are an opportunity to study the effect of single-clone malaria infections on the immune response. This proposed work will evaluate immune responses in malaria nave volunteers who experience single and repeated P. falciparum infections in order to inform the interpretation of immune responses in individuals living in malaria endemic regions. Protein and peptide microarrays will be used to probe sera from initially nave volunteers after they have recovered from P. falciparum challenge. Aim 1: Evaluate the effect of single infections on the immune response by comparing two groups of volunteers after infection with two different P. falciparum strains. Aim 2: Evaluate the effect of repeated infection on the immune response by following a group of volunteers who experience four P. falciparum infections over two years.